Conjugated acetylenic ketone and parasiticide thereof



United States Patent M 9,75 Int. Cl. C07d 63/12, 13/00, /16

US. Cl. 260-3323 4 Claims ABSTRACT OF THE DISCLOSURE A conjugated acetylenic ketone having the general formula R-SO-CEO-CEC-R' in which R and R is a heterocycle having a pentagonal, hexagonal or condensed nuclei heterocyclic residue containing a heteroatom of oxygen, sulphur or nitrogen and in which R represents in addition an organic group such as methyl, ethyl, phenyl, indenyl, naphthyl and anthracenyl and a parasiticide formed thereof.

This invention relates to a new family of compounds identified as conjugated acetylenic ketones in which the molecule contains one or more heterocycles having at least one heteroatom and it relates also a process for preparation of such compounds and the use of same as a parasiticide.

The anti-fungal activity of phenyl-l hexadiyne-2,4 one-1 is known; however, such compound has very little activity against parasitic fungi such as Trz'chophyton interdigitale, Aspergillus niger, Glomerella cingulata, etc. In order to obtain a desirable effect, large dosages of such compound are necessary.

0n the other hand, the compounds of this invention are highly effective thereby to enable use in relatively low concentrations for inhibiting parasitic organisms.

The compounds of this invention comprise conjugated acetylenic ketones containing one or several heterocycles having at least one heteroatom, as represented by the general formula and its isomer in which R and R' represent a pentagonal, hexagonal or condensed nuclei heterocyclic residue having at least one heteroatom such as oxygen, sulphur and nitrogen and having substituent groups such as alkyl, as represented by methyl, ethyl, butyl, propyl, isopropyl and the like; acyl, as represented by acetyl, propionyl, ethanoyl, isobutyryl and the like; halogeno, trihalogenomethyl, hydroxyl, alkoxyl as represented by methoxyl, ethoxy, butoxyl and the like, amino, amido, dialkylamino as represented by dimethylamino, diethylamino, ethylmethylamino and the like, dialkylamido and nitro groups. In addition, R can represent an alkyl group such as methyl, ethyl, or a radical having a simple or condensed benzenic nucleus such as phenyl, indenyl, naphthyl, anthracenyl, in which the henzenic nucleus may have substituent groups such as alkyl, acyl, halogeno, trihalogenomethyl, hydroxyl, alkoxyl, amino, 'amido, dialkylamino, dialkylamido and nitro groups, as previously defined for R.

Amongst the heterocyclic residues, reference can be made to the groups comprising at least one oxygen atom, such as derived from furan, pyran, coumarone; the groups comprising at least an atom of sulphur, such as derived from thiophene, thiopyran, thiocoumarone; the

3,463,788 Patented Aug. 26, 1969 groups comprising at least one nitrogen atom such as derived from pyrrol, pyridine, indol, quinoline, imidazole, pyrazole, triazole, tetrazole, diazines, triazines, tetrazines and the groups comprising several difierent hetero-atoms such as derived from oxazole, thiazole and furazan.

Among the different compounds corresponding to Formulae I and 11, reference is made particularly to (furyl-2)-1 hexadiyne-2,4-one-l; (thienyl-2)-1 hexadiyne- 2,4 one-l; and (dioxymethylene-3,4 phe=nyl)-1 hexadiyne- 2,4 one-l.

Applicants have found that the association of at least one heterocycle of the type described. with the ketone function and with the acetylenic bonds. confers onto the compound a parasitic activity of unexpectedly high efficiency.

The preparation of acetylenic ketones can be carried out by oxidation of the corresponding alcohols as by means of any classical oxidizing agent, such as chromic anhydride or active magnesium dioxide.

These corresponding alcohols can be obtained by several methods such as (a) by the action of the corresponding aldehyde on lithium or sodium derivatives of proper acetylenics in which the reaction is carried out in liquid ammonia or in any other convenient solvent, (b) by the action of the aldehyde on the magnesium derivative of the proper acetylenics, (c) by the action of the l-bromo acetylenic on the proper acetylenics according to the Cadiot and Chodkiewicz reaction, or (d) by action of an acetylenic magnesium derivative on a low alkyl formate, such as ethyl formate as in the case of the preparation of alcohols corresponding to the ketones of Formula II in which R is the same as R.

The conjugated acetylenic ketones of this invention, and particularly the (furyl-2)1 hexadiyne-2,4 one-1 and the (thienyl-2)-1 hexadiyne-2,4 one-1 have anti-fungal activity, especially with respect to Candida albicans, Sabouraudites gypseum, Scopulariopsis brevicaulis; T richophyton gypseum granulosum, Trichophyton interdigitale, Aspergillws nz'ger, Aspergillus versicolor, Cercospom malvacearum, Cercospora melonis, Erysiphe graminis, Glomerella cingulata; Plasmopara viticola, and towards the standardized mixture NF x 41-514.

Herbicidal activity has also been exhibited towards monocotyledone plants such as oats .and dicotyledone plants such as the nasturtium and mustard.

The acetylenic ketones of this invention can also advantageously be mixed with other known microbicides. They can be formulated for use in a solvent system such as acetone, benzene, chlorobenzene, chloroform, etc., or they may he applied in their pure state or in admixture with inert carriers such as talcum, sand, kaolin and the like for application as a powder. The compounds can be formulated into a paste or pomade for application.

The following examples are given by Way of illustration, but not by way of limitation, of the practice of this invention:

EXAMPLE 1 Preparation of (furyl-2)-1 hexadiyne-2,4 one-1 A solution of 16 g. of pentadiyne-l,3 in 25 m1. of anhydrous ether is added dropwise at room temperature to a ml. solution of anhydrous ether of magnesium ethyl bromide formed of 7 g. .of magnesium and 34 g. of ethyl bromide. The mixture is heated at reflux temperature until ethane is no longer given off.

The resulting solution of inagnesian derivative of pentadiyne-1,3 is cooled in a salt-ice bath solution to which 24 g. of freshly distilled furfuraldehyde is added slowly with constant agitation. After one hour of agitation, the solution is cooled to room temperature and allowed to stand over night. The derivative is hydrolyzed with the aid of an ice cold solution of ammonium chloride and then extracted with ether. The ether solution is washed with water, dried on sodium sulfate and the ether is then distilled off. After re-crystallization in the petroleum ether, 20 g. of (fury1-2)-1 hexadiyne-2,4 ol-l are obtained having a melting point of 63 C., corresponding to a yield of 50% by weight of theory.

10 g. of the alcohol are introduced into a suspension of 100 g. of active MnO in a liter of acetone which has previously been distilled on potassium permanganate. After 9 hours of agitation at room temperature, the product is filtered and the solvent is distilled off.

After re-crystallization in aqueous alcohol, 5.05 g. of (furyl-2)-1 hexadiyne-2,4 one-1 having a melting point of 73 C. are obtained, corresponding to a yield of 50.5% of theory.

EXAMPLE 2 The anti-fungal activity of the product of Example 1 has been determined on parasitic fungi.

For a first fungus group including Scopulariopsis breviczmlis and Triclzophyton interdigitale, the culture medium (a) is formulated of 100 ml. of Saubouraud medium gelosed at 2% while for a second group of fungus including As pergillus niger, Cercospora melonis, and Glomerella cingulata, the culture medium (b) is formulated of 100 ml. of malt agar.

The respective culture media were sterilized by autoclave at 110-12.0 C. for 20 minutes. To each of the sterilized media, there is added at the outlet of the autoclave, .5 ml. of acetone containing the compound of Example 1 in proportions ranging from one part of the compound to 1,000 to 100,000 parts by weight of the culture medium. The separate culture media are agitated and poured into previously sterilized Petri dishes. Two control samples are employed in which one contains the Sabouraud medium gelosed at 2% and to which .5 ml. of acetone has been added per 100 ml. of media while malt agar is added to the other with .5 ml. of acetone per 100 ml. of the medium.

After cooling, the boxes are implanted with approximately equal amounts of mycelium, taken from stock cultures. They are placed in a dry oven at 28 C. and examination was made after 10 days of incubation.

For purposes of comparison, identical tests were carried out with phenyl-l hexadiyne-2,4 one-l. The results which are given in the following table set forth the minimal concentration of the compound which operates completely to inhibit growth of the microorganisms after 10 days of incubation at 28-30 0.:

Minimal concentrations i (Furyl-2) -1 Phenyl-l hexadiyne -2,4 hexadiyne 2,4

Parasites one-1 one-1 Scapuluriopsis brez icaulz's .a 1, 32, 000 1/16, 000 Trichophyton interdigitale 1/40, 000 1/20, 000 Aspergz'llus m'ger 1/50. 000 1/12, 500 Cercospora melom's. 1/16, 000 1/4, 000 Glomerella cingulata 1/32, 000 1/16, 000

The results set forth in the foregoing table establish that the anti-fungal activity of the (furyl-2)-1 hexadiyne- 2,4 one-1 is two to four times greater than that of phenyl-1 hexadiyne-2,4 one-1.

EXAMPLE 3 The destructive coefficient was determined by comparison with untreated controls both 8 days and one month after treatment. After 8 days, a fading of the major part of the growth is noticed with the untreated plants and after one month all three of the plants exhibited noticeable yellowing.

EXAMPLE 4 Preparation of (thienyl-2)-1 hexadiyne-2,4 one-1 EXAMPLE 5 The anti-fungal activity of the compound of Example 4 was determined as in Example 2 using the culture medium (b). The minimal concentrations of compound for inhibiting the growth of the microorganisms are set forth in the following table using phenyl-l hexadiyne-2,4 one -1 as a comparison:

Minimal concentrations 01'- (Thienyl-2)-1 Phenyl -1 hexadiync-2,4 hexadiyne-2,4 Parasites of vegetables one-1 one-1 Aspergillus niger 1/50, 000 1/12, 500 Cercospom malvacsarum 1/64, 000 1/32, 000 Melange NF 2; 41-514 1/12, 500 1/6, 600

From the foregoing results, it will be obvious that the (thienyl-2)-l hexadiyne-2,4 one-1 is two to four times more active than the phenyl-l hexadiyne-2,4 one-1.

EXAMPLE 6 The procedure is the same as that set forth in Example 1. The magnesian derivative of pentadiyne-1,3 is obtained by reaction of 5.3 g. of magnesium, 26.2 g. of ethyl bromide and 12.2 g. of pentadiyne-1,3 in 200 ml. of anhydrous ether.

To the solution of the magnesian derivative of pentadiyne-1,3, 28.5 grams of piperonal are added and 39 g. of (dioxymethylene-3,4 phenyl)-1 hexadiyne-2,4 ol-l are obtained corresponding to a yield of 96% by weight of theory.

The alcohol is oxidized in the presence of 390 g. of active MnO in suspension in 3.9 liters of acetone. After recrystallization in a mixture of benzene and petroleum ether, 19.35 g. of (dioxymethylene-3,4 phenyl)-1 hexadiyne-2,4 one-1, having a melting point of 128 C., are obtained corresponding to a yield of 15% by weight of theory.

EXAMPLE 7 The anti-fungi activity of the product obtained in Example 6 was established on Aspergillus niger in the procedure set forth in Example 2 using the (b) culture medium. For purposes of comparison, identical tests were carried out with phenyl-l hexadidyne-2,4 one-1.

The minimal amount of (dioxymethylene-3,4 phenyl)- 1 hexadiyne-2,4 one-1 for completely inhibiting growth of Aspergillus niger was found to be one part per 25,000. This is to be compared with the amount of one part per 12,500 for the' (phenyl-l) hexadiyne-2,4 one-1, indicating that the compound of this invention is twice as effective towards Aspergillus niger as phenyl-l hexadiyne-2,4 one-1.

5 6 It will be understood that invention is to be found not References Cited only in the new and novel compounds produced in ac- Von Richter, The Chemistry of the Carbon cordance with the practice of this invention but also in pounds NY. Elsevier (1947) 1445' use as an ann'funglclde or parasltlclde' Tanaka et al.: Antibiotics and Chemotherapy, vol. 9,

We claim: 5 pp 151 5 (1959) I i a I for m 13a gl g ggf gi ffi g gi fi z i Guser et a1.: Chem. Abstracts, vol. 59, p. 3800 (1963). heterocycle selected from the g p consisting of y Nash et of Chem 2983 6 (1965).

thienyl and dioxymethylenephenyl and R is a radical selected from the group consisting of methyl and ethyl. 10 ALEX MAZEL Pnmary Exammer 2. The conjugated acetylenic ketone (furyl-2)-1 hexa- L DENTZ, Assistant E mi diyne-2,4 one-1.

3. The conjugated acetylenic ketone (thienyl 2) -1 y -zA one-1. 260-3405, 347.8; 424-285 4. The conjugated acetylenic ketone (dioxymethylene- 15 3,4 phenyl)-1 hexadiyne-2,4 one-1. 

